Key Points
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Induced pluripotent stem cells (iPSCs) that are derived from patients and differentiated in vitro can provide disease-relevant cell types for drug screening.
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Directed differentiation of iPSCs has yielded many disease-relevant cells — chiefly neurons, hepatocytes, blood cells and cardiomyocytes — but often the cells reflect embryonic stages of development, and may not faithfully reflect disease phenotypes of adult tissues.
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Methods for deriving iPSCs are evolving, and much remains to be learned about the genetic and epigenetic stability of iPSCs and their relationships to embryonic stem cells, and how this affects the fidelity of drug screening.
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Notwithstanding a few exceptions, disease modelling so far has focused on Mendelian disorders of high clinical penetrance and with a recognized cellular pathophysiology, such as spinal muscular atrophy, familial dysautonomia, Rett syndrome, Hutchinson–Gilford progeria syndrome and long QT syndrome. Whether more complex, sporadically occurring disease entities can be modelled with iPSCs remains uncertain.
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Cell-based assays enable the discovery of novel pathways and the identification of compounds with favourable cell permeability and toxicity profiles, but such assays are less amenable to defining the structure–activity relationships that are important for optimizing drug properties.
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iPSCs offer important advantages for drug toxicity screening against relevant human cells and tissues, and may facilitate the development of 'in vitro clinical trials' to test the efficacy of drugs or gene correction vectors against various distinct patient genotypes.
Abstract
The ability to generate induced pluripotent stem cells (iPSCs) from patients, and an increasingly refined capacity to differentiate these iPSCs into disease-relevant cell types, promises a new paradigm in drug development — one that positions human disease pathophysiology at the core of preclinical drug discovery. Disease models derived from iPSCs that manifest cellular disease phenotypes have been established for several monogenic diseases, but iPSCs can likewise be used for phenotype-based drug screens in complex diseases for which the underlying genetic mechanism is unknown. Here, we highlight recent advances as well as limitations in the use of iPSC technology for modelling a 'disease in a dish' and for testing compounds against human disease phenotypes in vitro. We discuss how iPSCs are being exploited to illuminate disease pathophysiology, identify novel drug targets and enhance the probability of clinical success of new drugs.
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Acknowledgements
The authors would like to especially thank S. Irion, E. Vaisberg, I. Griswold-Prenner and C. Johnson for their crucial input and help with writing the manuscript. Special thanks to A. Rosenthal for his help in editing and integrating the manuscript, and M. Smith and B. Keon for their help with the graphic design.
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Competing interests
Marica Grskovic and Ashkan Javaherian are both employed by iPierian, and Berta Strulovici is a former employee. George Q. Daley is on the scientific advisory board of iPierian. All co-authors hold equity in the company, which uses induced pluripotent stem cells to develop drugs against neurodegenerative diseases.
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Glossary
- Embryonic stem cells
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(ESCs). Pluripotent cells derived from a pre-implantation-stage embryo. These cells are capable of dividing without differentiating for a prolonged period in culture.
- Induced pluripotent stem cells
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(iPSCs). Pluripotent cells derived from differentiated somatic cells through treatment with exogenous factors.
- Disease phenotype
-
A molecular, cellular or functional manifestation of a disease in patient-derived cells.
- Pluripotent stem cells
-
(PSCs). Undifferentiated cells that have the ability to self-renew and the potential to differentiate into cells of the three primary germ layers: endoderm, mesoderm or ectoderm.
- Embryoid bodies
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Aggregates of cells derived from pluripotent cells, formed by growing pluripotent cells in suspension in the absence of self-renewal-promoting factors. Following their aggregation, these cells differentiate into various differentiated cell types partly recapitulating early embryonic development.
- Reprogramming
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The process by which a differentiated somatic cell acquires the features of a pluripotent stem cell or a differentiated cell of a different cell type.
- Spinal muscular atrophy
-
A monogenic neurodevelopmental disorder in which a reduced level of survival of motor neuron (SMN) protein leads to the degeneration of motor neurons during childhood.
- Epigenetic
-
A heritable change in gene expression that is not caused by the DNA sequence.
- Copy number variations
-
Duplications or deletions in the genome that lead to variability in the number of genes.
- LEOPARD syndrome
-
An autosomal dominant multisystem disease caused by a mutation in the gene encoding protein tyrosine phosphatase non-receptor type 11. The disease affects the skin as well as the skeletal and cardiovascular systems.
- QT interval
-
A measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart.
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Grskovic, M., Javaherian, A., Strulovici, B. et al. Induced pluripotent stem cells — opportunities for disease modelling and drug discovery. Nat Rev Drug Discov 10, 915–929 (2011). https://doi.org/10.1038/nrd3577
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DOI: https://doi.org/10.1038/nrd3577
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